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bioRxiv · 10.64898/2026.05.08.723911

Immune receptor LAG3 regulates microglia function duringAlzheimer's disease

Perl, A. T.·Wu, J.·Dong, J. D.·Brooks, A. M.·Yoblinski, A. R.·Vierling, T. T.·Li, J.-L.·Ruby, D. R.·Radzicki, D.·Dudek, S. M.·Cushman, J. D.·Gjoneska, E.
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Abstract

Alzheimers Disease (AD) remains the leading cause of dementia globally, yet the exact etiology is not well defined and effective treatments remain unavailable. Here, we report that deletion of the immune checkpoint receptor lymphocyte activation gene 3 (Lag3) in a familial AD mouse model, 5xFAD+, can rescue molecular, cellular and behavioral phenotypes of neurodegeneration. Specifically, we demonstrate that amyloidosis and microgliosis in the 5xFAD+ mice are significantly reduced by Lag3 deletion. Moreover, we show that Lag3 deletion attenuates deficits in neurodegeneration-related behavioral phenotypes in the 5xFAD+ mice. Transcriptional profiling reveals that Lag3 deletion suppresses aberrant overexpression of disease associated microglia (DAM) genes in 5xFAD+ microglia, effectively restoring homeostatic transcriptional programs. Finally, we observe reduced CD8+ T cell infiltration in the brain of 5xFAD+ animals after Lag3 deletion which likely mediates molecular, cellular and behavioral effects resulting from microglia DAM gene activation. Our results highlight a previously unrecognized role for Lag3 in AD as a critical regulator of microglia function and suggest Lag3 might be a viable target for novel AD therapeutic interventions. HighlightsO_LIImmune receptor Lag3 deletion ameliorates amyloidosis and microgliosis during AD C_LIO_LILag3 deletion attenuates deficits in neurodegeneration-related behavioral phenotypes C_LIO_LILag3 deletion reverses aberrant activation of DAM genes and restores microglia homeostasis C_LIO_LILag3 inhibition presents a viable approach for novel AD therapeutic interventions C_LI

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Perl, A. T., Wu, J., Dong, J. D., Brooks, A. M., Yoblinski, A. R., Vierling, T. T., Li, J.-L., Ruby, D. R., Radzicki, D., Dudek, S. M., Cushman, J. D., Gjoneska, E.. 2026-05-12. Immune receptor LAG3 regulates microglia function duringAlzheimer's disease. https://doi.org/10.64898/2026.05.08.723911

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